CN1222318C - Cellulosic particle for pharmaceutical preparation - Google Patents

Abstract

Cellulose particles for pharmaceutical, which contains microcrystalline cellulose having an average degree of polymerization of from 60 to 350 in an amount of not less than 10%, and which have a tapped bulk density of from 0.60 to 0.95 g/ml, an aspect ratio of not less than 0.7, a shape factor of from 1.10 to 1.50, and an average particle size of from 10 to 400 mu m.

Description

Cellulose particles for preparation

technical field

The present invention relates to cellulose particles for formulations, methods for their preparation, methods for their use and active ingredient-containing granules produced from these cellulose particles.

Background technique

Various methods can be used in preparing the granules comprising the active ingredient. In recent years, a method involving layering active ingredients on particles has been proposed. Especially since improvements in pharmaceutical machinery have made it possible to layer large quantities of active ingredients onto relatively small particles. As a result, various methods of layering the active ingredient have been proposed.

For example, JP-A 61-1614 discloses a method comprising layering active ingredients on carbohydrate core particles; JP-A 7-173050 and JP-A 4-283520 disclose methods involving layering active ingredients on spherical A method on a core, and JP-A 2000-109426 discloses a method comprising layering an active ingredient on microcrystalline cellulose.

However, the sugar core particle disclosed in JP-A 61-1614 has some problems as follows:

(1) It is difficult to prepare core particles having a small particle size suitable for active component layering,

(2) When the layering of the active ingredient is carried out with the saccharide core particle and the aqueous active ingredient suspension, the sugar which is the main component of the core particle dissolves itself to make the surface sticky, thereby making the core particle The particles themselves tend to aggregate, and

(3) The strength of the core particles is weak, and it is easy to wear during the fluidization process, and at the same time, the aggregation of the core particles itself and the phenomenon that the core particles are attached to the wall of the coating machine are easy to occur, so the yield becomes poor.

Furthermore, in the case where the spherical core disclosed in JP-A 7-173050 or JP-A 4-283520 is used as the core, this type of spherical core also has some problems as follows:

(1) Although the spherical core is hardly worn due to its anti-wear ability and has excellent fluidity, in order to ensure the fluidity required for active ingredient layering, it is necessary to increase the air supply rate, and due to the fluidization process The air flow or the collision between the cores caused by their own weight makes the layered active ingredients easy to peel off,

(2) Although the spherical core has excellent water absorption, aggregation tends to occur in the early stage of layering when the spray speed of the aqueous active ingredient suspension is increased because its surface is flat, and

(3) When used in the preparation of a rapidly dissolving tablet in the mouth, since the strength of the spherical core is too large, the tongue feels rough when administered.

In addition, when microcrystalline cellulose is used as the core as disclosed in JP-A 2000-109426, there is still the problem that the active ingredient is not easily layered, because

(1) The particles have a low tapped bulk density so that they can attach to any bag filter in the upper part of the coating machine when supplied with an airflow at a flow rate suitable for layering of the active ingredient,

(2) It has a large angle of repose, so its fluidity in the coating machine becomes poor, and

(3) It is easily attrited, so particles with a narrow particle size distribution cannot be obtained.

Disclosure of the invention

In view of these present circumstances, the present invention has been accomplished through extensive studies on the properties of particles used in the field of pharmacy.

That is, the present invention provides

(1) Cellulose particles for formulations comprising not less than 10% of microcrystalline cellulose having an average degree of polymerization of 60 to 350, and which have a tapped bulk density of 0.60 to 0.95 g/ml, an aspect ratio of Not less than 0.7, a shape factor of 1.10 to 1.50, and an average particle size of 10 to 400 μm;

(2) A method of producing cellulose particles for preparations as described in (1) above, the method comprising the steps of: hydrolyzing a cellulose substance to obtain an average degree of polymerization of 60 to 350, and then mechanically grinding the thus hydrolyzed product and obtaining an average particle diameter of not higher than 15 μm; preparing a dispersion comprising the obtained microcrystalline cellulose; forming said dispersion into droplets; then drying said droplets; and

(3) Spherical particles characterized in that a drug is contained on the surface or inside of the particle for formulation as described in (1) above.

Best Mode for Carrying Out the Invention

The cellulose particles for formulations of the present invention contain microcrystalline cellulose having an average degree of polymerization of 60 to 350 (hereinafter simply referred to as microcrystalline cellulose) in an amount of not less than 10%. When the content of the microcrystalline cellulose is not less than 10%, the particles can have appropriate strength, and can reduce loss due to friction during active ingredient layering. From the viewpoint of particle strength and friction resistance, it is preferable that the cellulose particles for formulation contain microcrystalline cellulose in an amount of not less than 30%, preferably not less than 50%, and more preferably not less than 70%. From the viewpoint of simplification of the pharmaceutical preparation, 100% microcrystalline cellulose is most preferred. A microcrystalline cellulose content lower than 10% is not recommended because the particle strength will be low if it is lower than 10%, and the loss due to friction is large.

The microcrystalline cellulose used has an average degree of polymerization of 60 to 350. It can be obtained by hydrolyzing cellulosic materials such as linters, pulp or regenerated fibers, such as acid hydrolysis, alkali hydrolysis, steam explosion decomposition or a combination of two or three of these methods. Alternatively, mechanical treatment such as pulverization may be performed before or after the above-mentioned chemical treatment.

An average degree of polymerization of more than 350 is not recommended because of the observation of fibrous properties, making it difficult to grind the microcrystalline cellulose, and furthermore, the aspect ratio decreases. It is not recommended that the average degree of polymerization be lower than 60 because the degree of entanglement of cellulose molecules decreases, thereby making the hardness of the cellulose particles for formulation insufficient. The preferred average degree of polymerization is 100 to 270, more preferably 120 to 200.

Components other than microcrystalline cellulose may also be added to the particles. Examples thereof are binders (such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, etc.), film coating agents (such as hydroxypropyl phthalate Methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, ethyl cellulose, ethyl cellulose aqueous dispersion, aminoalkyl methacrylate copolymer E, methyl Acrylic acid copolymer L, methacrylic acid copolymer S, methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer RS, hardened oil, etc.), surfactants (such as sucrose fatty acid ester, polyoxyethylene poly Oxypropylene glycol, polysorbate, sodium lauryl sulfate, etc.), excipients (such as corn starch, potato starch, rice starch, powdered sugar, lactose, D-mannitol, trehalose, microcrystalline cellulose and sodium carboxymethylcellulose, etc.), disintegrants (such as low-substituted hydroxypropyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, pregelatinized starch, etc.), inorganic substances ( Such as talc, magnesium stearate, light silicic anhydride, synthetic aluminum silicate, titanium oxide, etc.), and other commonly used additives in preparations.

The cellulose particles for formulation of the present invention have a tapped bulk density of 0.60 to 0.95 g/ml. A tapped bulk density below 0.60 g/ml is not recommended because such particles are so light that it is necessary to reduce the amount of such particles that are fed into the layerer. In addition, this density is not recommended because at air volume conditions suitable for active ingredient layering, the particles will adhere to any bag filter installed in the upper part of the coater, resulting in a decrease in yield. In addition, tapping bulk densities in excess of 0.95 g/ml are not recommended because such particles are so heavy that it is necessary to greatly increase the air volume required for particle fluidization suitable for active ingredient layering. As a result, the active ingredient is easily peeled off due to the high air volume, so that the layering of the active ingredient fluctuates. A preferred tapped bulk density is from 0.60 to 0.90 g/ml. More preferably 0.60 to 0.85 g/ml, and particularly preferably 0.65-0.85 g/ml.

The cellulose particles for formulations of the present invention have an aspect ratio of not less than 0.70. When the aspect ratio is less than 0.7, the aspect ratio of the particles after the active ingredient is layered becomes poor, which is not desirable from the viewpoint of product aesthetics. Preferably the aspect ratio is not lower than 0.75, more preferably not lower than 0.80.

In the present invention, the cellulose particles for formulations have a shape factor of 1.10 to 1.50. A shape factor below 1.10 is not recommended because the surface of each particle is smooth, making it difficult for aqueous active ingredient suspensions or binder solutions to adhere. Increasing the spray rate is not recommended as it tends to aggregate during layering. On the other hand, a shape factor higher than 1.50 is not recommended because the surface of such particles has too many bumps, so that the active ingredient layered particles have more bumps and bumps, which reduces the aesthetics of the particles. Furthermore, the reason why a shape factor higher than 1.50 is not recommended is also that such particles are prone to wear when subjected to friction, which tends to cause particle aggregation and thus wide particle size distribution. In addition, coating granules with a large number of concavities and concavities is not recommended because it is difficult to control the release rate of the active ingredient. A preferred shape factor is 1.15 to 1.50, more preferably 1.15 to 1.45.

In the present invention, the cellulose particles for formulations have an average particle diameter of 10 to 400 μm. Average particle sizes below 10 μm are not recommended because of the difficulty in layering of the active ingredient and the tendency of the particles themselves to agglomerate. In addition, an average particle size higher than 400 μm is also not recommended because it produces layered particles with a large particle size, which may give a rough feeling to the tongue, thus deteriorating the dosability. Furthermore, such a large particle size can lead to content fluctuations when used in the preparation of tablets comprising granules. In addition, it is not recommended because the amount of active ingredient that can be layered is limited when it is necessary to use small particle size particles. The average particle diameter is preferably 40 to 400 μm, more preferably 50 to 400 μm, still more preferably 50 to 300 μm, particularly preferably 50 to 200 μm.

Preferably, the cellulose particles for formulations of the present invention have a specific surface area of 0.15 to 0.60 m ² /g. A specific surface area of less than 0.15 m ² /g is not preferred because then the particle surface becomes smooth, making it difficult for an aqueous active ingredient suspension or binder solution to adhere thereto. Increasing the spray rate is not preferred because aggregation tends to occur during layering. Specific surface areas higher than 0.60 m ² /g are not preferred because particles are subject to friction and tend to be attrited, thereby causing particle aggregation and thus producing particles with a broad, non-uniform particle size distribution.

Preferably, the cellulose particles for formulations of the present invention have a moisture adsorption capacity of not less than 1.50%. It is preferable that the moisture absorption amount is not lower than 1.50%, because if the water absorption is insufficient, when the suspension of the active ingredient is sprayed or when the layering of the active ingredient is performed with an aqueous binder solution, aggregation of particles may be caused and It will be attached to the wall of the coater.

Preferably, the cellulose particles for formulation of the present invention have a peak load of 130 to 630 mN. The load peak value lower than 130mN is not preferred because the strength of such particles is insufficient, so the particles are easily worn due to friction or impact during the layering process, resulting in aggregation of particles, so the manufactured particles have wide and uneven Particle size distribution. Load peaks above 630 mN are not preferred because the strength of such particles is too great, causing a rough feeling on the tongue when administered.

Preferably, the cellulose particles for formulation of the present invention have an angle of repose not higher than 41°. An angle of repose exceeding 41° is not preferred because such particles have poor fluidity, so that aggregation of the particles occurs during the layering of the active ingredient. More preferably, the angle of repose is not higher than 39°, and even more preferably not higher than 37°.

It is desirable that the cellulose particles used in the preparation have low brittleness. High brittleness is undesirable because particles with high brittleness are prone to wear when subjected to friction, resulting in aggregation of particles, thus producing particles with a broad and non-uniform particle size distribution.

The method for producing the cellulose particles for formulation of the present invention should include a wet milling step and a spray drying step as described below. When using a method comprising these two steps, formulation cellulose particles having the physical properties defined herein can be obtained. Otherwise, it is difficult to obtain the cellulose particles for formulation of the present invention, especially to obtain cellulose particles satisfying the requirements of having a relatively small average particle diameter and a large shape coefficient at the same time.

For example, the cellulose particles for pharmaceutical preparations of the present invention can be produced by the following method.

First, cellulosic materials such as linters, pulp, and regenerated fibers are subjected to hydrolysis, such as acid hydrolysis, alkali hydrolysis, steam explosion decomposition, or a combination of two or three of these, to obtain a degree of polymerization of 60 to 350. Before carrying out the hydrolysis, mechanical treatment as described below may be carried out. The dispersion of cellulose itself obtained by filtering, washing or decanting the resulting hydrolyzed mixture preferably has an electrical conductivity of not higher than 300 μS/cm. A conductivity exceeding 300 [mu]S/cm is not preferred because impurities generated upon hydrolysis contaminate the cellulose particles used in the formulation. The dispersion is purified to obtain a conductivity preferably not higher than 150 μS/cm, and particularly preferably not higher than 75 μS/cm, so that a cake-like product can be obtained, which is then used for Subsequent wet grinding step.

In the wet milling step, the cake-like product obtained above is mechanically treated, for example by milling. Alternatively it can be converted into a dispersion comprising the cake-like product, which is then treated mechanically, eg by grinding. Alternatively, they can be processed by their combination. Thus, the particle diameter of microcrystalline cellulose in the cellulose dispersion is not higher than 15 μm. It is not recommended that the particle size exceed 15 μm, because if the particle size exceeds 15 μm, the tapping bulk density of the cellulose particles for the formulation will become low, and the particle strength will decrease at the same time. The particle size is preferably not more than 13 μm, more preferably not more than 10 μm.

When purification is performed by decantation or the like, the cellulose dispersion may be mechanically treated as it is.

Alternatively, the microcrystalline cellulose powder obtained by drying the cellulose dispersion may be pulverized or ground as described above, and then mixed with water to obtain a desired particle size. Alternatively the powder can be mixed with water to obtain a suspension which is then subjected to milling as described above to obtain the desired particle size. Alternatively, the powder can be treated with a combination of the above methods. Furthermore, once dried, powder obtained by pulverizing or grinding microcrystalline cellulose may be mixed with microcrystalline cellulose whose particle size has been adjusted by wet grinding after hydrolysis to obtain a cellulose dispersion.

This mechanical treatment can be performed by a conventional method. One embodiment is as follows. When the cake-like product is processed, a mixing mixer (for example, a universal mixing mixer, etc.) or a kneading and grinding machine (for example, a mortar, a kneader, etc.) can be used, for example, at 25 to 80%, preferably 30 to 60%. The solid content is crushed. When the dispersion is processed, a mixing and dispersing machine (such as a homogenizer, a high-pressure homogenizer, etc.) or a media mill (such as a wet vibrating mill, a wet planetary vibrating mill, a wet ball mill, a wet paint vibrator) can be used etc.), pulverization is carried out at a solid content of 1 to 30%.

The resulting milled cake-like product and the dispersion comprising milled cellulose are diluted to a concentration of about 1 to 25%, thereby obtaining a dispersion of cellulose itself, the particle size of which can be easily controlled in a drying process as described below. The desired particle size in the step. The pH of the dispersion of the cellulose itself is adjusted to 5 to 8.5.

When other components other than microcrystalline cellulose are contained, the active component may be mixed with the cake product after hydrolysis, or the active component may be mixed with the cellulose dispersion obtained by the above method .

Subsequently, the aforementioned cellulose dispersion liquid is converted into liquid droplets, which are then dried by spray drying using a rotating disc, double-flow paired nozzles, pressure nozzles, and the like.

The machinery used for spray drying and the method of spray drying are not limited. However, from the viewpoint of imparting properties to the cellulose particles for formulations of the present invention, a spray-drying method using a rotating disk is recommended. In the spray drying process using a rotating disk, the liquid feed rate, the solid content of the liquid, the diameter of the rotating disk, the speed of the rotating disk and the drying temperature are not particularly limited. One embodiment is as follows. The dispersion liquid containing microcrystalline cellulose having a solid content greater than or equal to 1% is supplied to a rotating disk with a diameter of 3 to 50 cm, and the rotating disk is rotated at a speed of 500 to 30000 rpm while controlling the feed rate of the liquid and drying temperature to obtain the desired particle size.

The solids content in the microcrystalline cellulose dispersion for spray drying is preferably 1 to 25%. The solid content is preferably equal to or higher than 1%, because it is difficult to obtain microcrystalline cellulose particles having a desired particle size if aggregation of the particles is insufficient. And it is also preferable from the standpoint of drying efficiency. On the other hand, a solid content exceeding 25% is not preferable because the viscosity of the cellulose dispersion increases when the solid content exceeds 25%, and thus coarse particles tend to be generated after drying. The solids content is more preferably 3 to 20%, most preferably 5 to 20%.

The loss on drying of the cellulose particles for pharmaceutical preparations after drying is preferably not higher than 10%, more preferably not higher than 7%, particularly preferably not higher than 5%.

After spray drying is complete, if necessary, sieving and sizing can be performed to limit the average particle size to 10 to 400 μm. From the viewpoint of the properties of the cellulose for formulation, a narrow particle size distribution is preferred.

The cellulose particles for formulations of the present invention can be produced by drying a dispersion containing microcrystalline cellulose ground to a desired particle size to aggregate into droplets. Therefore, it has high aspect ratio, high tapping bulk density, suitable shape factor, easy-to-adjust particle size distribution, suitable specific surface area, high water vapor adsorption capacity and suitable particle strength.

In order to layer the active ingredient on the cellulose particles for formulation, conventional methods can be used. The active ingredient can be layered by the method described below, but the method is not limiting of the manner in which the invention can be practiced.

That is, (1) a method, the method comprising using a fluidized bed granulation coating device (or rotary fluidized bed type granulation coating device, a fluidized bed granulation coating device equipped with Wuster's (Wurster) column) Granule coating equipment or a fluidized bed granulation coating equipment equipped with a modified Wuster column) while fluidizing the cellulose particles for formulation, the active ingredient will be dissolved or suspended in the solution of the binder to form The prepared liquid is used for spray formulations, (2) a method comprising continuously spraying a solution of a binder while simultaneously spraying microcrystalline cellulose particles for formulations in a centrifugal fluidized coating device A powder of the active ingredient (and excipients, if desired) for dosing formulation, (3) a method comprising adding an absorbable particle while rotating the cellulose particles with a high-speed mixing and granulating device Amounts of an active ingredient and a binder solution, and (4) a method comprising immersing cellulose particles for formulation into the active ingredient and a binder solution. In either method, when necessary, operations such as removal of dried aggregated particles may be performed.

The active ingredients used in the present invention are active substances for the treatment, prevention or diagnosis of human or animal diseases.

Examples of such active ingredients are antiepileptic drugs (acetophenbutamide, primidone, etc.), antipyretics, analgesics and anti-inflammatory drugs (acetaminophen, phenylacetylglycine dimethylamide, diclofenac, hydroxy Butazone, sulpyrine, ibuprofen, ketoprofen, tinolidine hydrochloride, benzydamine hydrochloride, thiramide hydrochloride, piroxicam, etc.), anti-vertigo drugs (Chengyunning, Vertigo, etc.) , psychiatric drugs (chlorpromazine hydrochloride, levomepromazine maleate, perazine maleate, perphenazine, diazepam, oxazepam, etc.), skeletal muscle relaxants (chlorzoxazone , chlorphenesin carbamate, clomezadone, eperisone hydrochloride, etc.), autonomic nervous system drugs (methacholine, neostigmine bromide, pyridostigmine bromide, etc.), Antispasmodics (butropium bromide, N-butyl scopolamine bromide, propantheline bromide, papaverine hydrochloride, etc.), antiparkinsonian drugs (trihexyphenidyl hydrochloride, etc.), antihistamines (diphenhydramine hydrochloride, dl-malenamine, d-malenamine salt, promethazine, mequitazine, etc.), cardiotonic agents (aminophylline, caffeine, dl-isoproterenol hydrochloride, Ethylfurin hydrochloride, etc.), antiarrhythmic drugs (disopyramide, etc.), diuretics (potassium chloride, hydrochlorothiazide, acetazolamide, etc.), hypotensive drugs (hexamethylammonium bromide, hydralazine hydrochloride, hydrochloric acid propranolol, captopril, methyldopa, etc.), vasodilators (etabenone hydrochloride, carbomer hydrochloride, pentyl tetranitrate, dipyridamole, nicotinamide ethyl citrate ( nicametate citrate), etc.), arteriosclerosis drugs (lecithin, etc.), circulatory organ drugs (nicardipine hydrochloride, meclofenoxate hydrochloride, pyroxate, calcium hopantenate, pentoxifylline, etc.), Respiratory accelerators (resulphin hydrochloride, etc.), antitussive and expectorant drugs (dextromethorphan hydrobromide, narcotin, L-cysteine methyl ester hydrochloride, theophylline, ephedrine hydrochloride, etc.), diuretics Bile drugs (dehydrocholic acid, etc.), gastrointestinal drugs (metoclopramide, domperidone, etc.), vitamins (furultiamine, octotiamine, pyridoxine hydrochloride, niacin, ascorbic acid, etc.) , antibiotics (erythromycin, kitasamycin, josamycin, tetracycline, etc.) and chemotherapy drugs (isoniazid, ethionamide, nitrofurantoin, enoxacin, ofloxacin, norfloxacin star, etc.). In the present invention, two or more active ingredients may be simultaneously layered or formed into another layer after forming one layer.

The amount of active ingredient to be layered is dose dependent. In addition, the amount mentioned here refers to the amount of the active ingredient layered on the surface of the cellulose for formulation. The following embodiment will be described in detail. When the action of the active ingredient can be expected even at very low doses, the amount to be layered is about 0.01% by weight, based on the weight of the starting granules. When a large dose is required to obtain the effect of the active ingredient, this amount is about 500% by weight.

When the active ingredient is layered on the cellulose particles for formulation, the active ingredient can be layered together with additives to facilitate each operation, prevent the active ingredient from peeling off during subsequent operations, control the dissolution rate of the active ingredient, or enhance stability sex. Examples of additives are: binders (such as hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinyl alcohol, polyvinylpyrrolidone, polyethylene glycol, etc.), film coating agents (such as hydroxyphthalic acid Propyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl cellulose, ethyl cellulose, ethyl cellulose aqueous dispersion, aminoalkyl methacrylate copolymer E, methyl Acrylic acid copolymer L, methacrylic acid copolymer S, methacrylic acid copolymer LD, aminoalkyl methacrylate copolymer RS, hardened oil, etc.), surfactants (such as sucrose fatty acid ester, polyoxyethylene polyoxy Propylene glycol, polysorbate, sodium lauryl sulfate, etc.), excipients (such as corn starch, rice starch, powdered sugar, lactose, microcrystalline cellulose, powdered cellulose, microcrystalline cellulose, and carboxymethyl cellulose sodium, etc.), disintegrants (such as low-substituted hydroxypropyl cellulose, carmellose calcium, croscarmellose sodium, pregelatinized starch, etc.), inorganic substances (such as talc, hard Magnesium fatty acid, light silicic anhydride, synthetic aluminum silicate, titanium oxide, etc.), and other substances.

The medium used in the layering of the active ingredient is not limited. Water, ethanol, and other organic solvents suitable for formulation can be used. Layering can be performed using a liquid prepared by dissolving or dispersing an active ingredient and a binder in a solvent.

A preferred method is as follows. In order to improve the ease of administration, improve the appearance, moisture-proof, anti-oxidation, adjust the dissolution rate of active ingredients (for example, to prepare controlled-release drugs or enteric-coated drugs), or to mask the bitter taste or odor of active ingredients, water-based coatings or solvent coatings can be used. Films are applied to granules prepared by layering the active ingredient onto the cellulose particles of the invention.

The film coating agent used for this type of film coating may be a conventional film coating agent. Examples thereof are water-soluble film coating agents (such as aminoalkyl methacrylate copolymer E, hydroxypropyl cellulose, hydroxypropyl methylcellulose, etc.), controlled-release film coating agents (such as ethyl cellulose , ethyl cellulose aqueous dispersion, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer RS, ethyl acrylate-methyl methacrylate copolymer emulsion, etc.), and enteric film coating agent ( For example, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, etc.). In addition, the above-mentioned coating agents can be used alone or in combination of two or more of the above-mentioned coating agents for coating. If necessary, other water-soluble materials can also be used at the same time to complete the masking of bitterness, odor, Moisture-proof and anti-oxidation purpose. However, the film coating agents are not limited to those listed here.

For coating the films containing the abovementioned film coating agents, conventional means can be used. Conventional means include fluidized bed granulation coating equipment, fluidized bed granulation coating equipment equipped with Wuster column or fluidized bed granulation coating equipment equipped with improved Wuster column, centrifugal Fluidized bed type granulation coating equipment and rotary fluidized bed type granulation coating equipment.

The layered active ingredient-carrying granules of the present invention or film-coated granules obtained by film-coating the layered active ingredient-carrying granules for the purpose of controlling the dissolution rate and the like can be directly administered. Alternatively, it may be administered after being encapsulated or mixed with other drugs. Alternatively, they can be mixed with other excipients, active ingredients, active ingredient-containing granules or film-coated granules, which can then be prepared into tablets to be used in the form of granule-containing tablets.

The method used for the determination of cellulose particles for pharmaceutical formulations is summarized as follows:

· Degree of polymerization of microcrystalline cellulose

The test for determination of microcrystalline cellulose described in the Japanese Pharmacopoeia, 13th edition (3) was used.

・Particle size of ground particles [μm]

Dilute the cellulose aqueous dispersion before drying with water to obtain a concentration that exhibits a suitable light transmittance, and after ultrasonication for one minute, use a laser diffraction type laser while stirring the diluted dispersion. A particle size distribution analyzer (LA-910 type, manufactured by Horiba, Ltd.) measures the volume-based average particle size under the conditions of a relative refractive index of 1.2 and an uptake number of 10.

·pH

The aqueous cellulose dispersion before drying was adjusted to 25°C, and then its pH was measured with a glass electrode type hydrogen ion density meter (D-21 type, manufactured by Horiba, Ltd.).

·Conductivity (IC)[μS/cm]

The aqueous cellulose dispersion before drying was adjusted to 25° C., and then its electrical conductivity was measured with an electrical conductivity measuring device (D-21 model, manufactured by Horiba, Ltd.).

· Tapping bulk density of cellulose particles for formulations

Thirty grams of particles are roughly filled into a 100ml glass graduated cylinder and tapped manually on a low-impact support such as a rubber-covered table. The cylinder is tapped and dropped vertically onto the support from a height of a few centimeters until the particles are no longer compressed. After tapping is complete, measure the volume of the particle layer and divide it by 30. The determination was repeated three times and the results were averaged.

·Aspect ratio of cellulose particles for formulation

Images taken with a digital microscope (type VH-7000 with VH-501 lens, manufactured by KEYENCE Co.) were stored in the form of TIFF files with a pixel size of 1360 × 1024, and then processed and analyzed with an image processing software (Image Hyper II , developed by DegiMo Co.), 100 particles were processed to obtain the aspect ratio (short diameter/long diameter) of their cross-sections, and the obtained results were averaged.

·Shape factor of cellulose for preparation

Images taken with a digital microscope (type VH-7000 with VH-501 lens, manufactured by KEYENCE Co.) were stored in the form of TIFF files with a pixel size of 1360×1024, and then image processing and analysis software was used to analyze 100 Particles are processed to obtain their shape coefficients, and the results are averaged. The shape factor can be obtained using the following equation. The value is 1 when there is no bump on a ball. This value increases as the bump increases, i.e. greater than 1.

Shape factor = (perimeter of particle) 2 / (4π × (sum of particle area)

・Average size of cellulose particles for pharmaceutical preparations [μm]

Using a Ro-Tap sieve shaker (A type sieve shaker, manufactured by Hirako Seisaku-sho Co., Ltd.), a sample (30 g) was sieved with a JIS standard sieve (Z8801-1987) for 15 minutes to measure the particle size distribution. The cumulative particle size of 50% by weight was taken as the average particle size. The measurements were repeated three times and the results obtained were averaged.

When the average particle size of the cellulose for formulation is less than 38 μm, the particles are dispersed in water. Thereafter, the average particle diameter thereof was measured according to the above-mentioned method for measuring the particle diameter of the ground particles.

・Specific surface area of cellulose particles for formulation

The sample was dried at 105°C for 3 hours in a blast constant temperature dryer (FC-610 type, manufactured by Toyo Seisakusho Kaisha, Ltd.), and fed into a measurement cell in such a manner that the wind flow path was ensured. )middle. The chamber was installed on a degassing section of a flow type automatic specific surface area measuring device (Flowsorb 2300, manufactured by Shimadzu Corporation), and then degassed at 120°C for 15 minutes with a jacketed heater. The specific surface area was measured at a flow ratio of nitrogen/(nitrogen+helium)=0.3 after removing moisture adhering to the chamber wall. The determination was repeated three times and the results obtained were averaged.

· Moisture adsorption of cellulose particles for preparations

The samples were dried at 105° C. for 3 hours in a forced air constant temperature dryer. Thereafter, the sample (about 30 g) was placed in a dynamic vapor absorption measuring device (DVS-1 type, manufactured by Surface Measurement Systems Ltd.), and then set at 25° C., a nitrogen atmosphere, and a relative humidity (RH) of 0%. Drying is carried out under the same conditions until the weight of the particles fully reaches a constant weight (the weight fluctuation is not higher than 0.02%). Thereafter, the relative humidity was set at 5% RH, and it was left to equilibrium (weight fluctuation not exceeding 0.02%). Subsequently, the relative humidity was set at 10%, and it was brought to equilibrium (weight fluctuation not exceeding 0.02%). Thereafter, each time the relative humidity is changed by 5%, the operation is repeated, that is, the process is repeated at 15%RH, 20%RH, 25%RH, 30%RH and 35%RH, thereby obtaining the relative humidity at 30% The difference between the particle weight at humidity and the particle weight at 0% relative humidity. The ratio of this weight difference to the particle weight at 0% relative humidity was defined as the water vapor adsorption. The determination was repeated three times and the results obtained were averaged.

·Peak loading of cellulose for formulations

These values were measured with a grain strength measuring device (GRANO, manufactured by Okada Seiko Co., Ltd.) at a measuring speed of 250 μm/sec, and the inflection point of the slope in the relative displacement and load waveform was taken as the load value. At a displacement of less than or equal to 50% of the particle size of the measured particle, there will be no observations within the displacement width of two or three times the minimum moving distance (1 μm) of the top chip (chip) of the particle strength measuring instrument. The point at which the load changes, or the first point at which the load begins to drop within the same displacement width, is taken as the point of inflection. The inflection point is determined for one hundred particles and then averaged.

・Angle of repose of cellulose particles for formulations (°)

The measurement was performed with a powder analyzer (PT-R type, manufactured by Hosokawamicron Co.) and the measurement was repeated three times. The obtained results were averaged.

The present invention will be explained in detail with reference to the following examples.

Example 1

Commercially available kraft pulp (abbreviated as KP hereinafter) was cut into pieces, and then hydrolyzed in 10% hydrochloric acid aqueous solution at 105° C. for 30 minutes. The resulting acid-insoluble residue was filtered and washed with water to obtain a cake-like product of microcrystalline cellulose having a solids concentration of about 40%. The cake-like product was found to have a degree of polymerization of 153. As shown in Table 1, the degree of polymerization was the same as that of particles obtained by grinding and drying the cake-like product. The cake-like product was ground with a universal mixer (5DM-03R type, manufactured by Sanei Seisakujo Co.) for 1 hour. Add water to it. A mixture of the pulverized cake product and water was prepared with a homomixer (T.K.HOMO MIXER MARK2II type, manufactured by TokushuKika Kogyo Co., Ltd.) into a cellulose dispersion having a solid content of 12.5% by weight. After adjusting the particle size, pH and IC, the dispersion is spray-dried with a rotating disk of about 8 cm. The drying operating conditions are that the rotation speed of the disk is about 5000 rpm, the flow rate is about 6 l/hour, and the air supply temperature is about 170 ° C. , the exhaust temperature is about 85°C. Coarse particles were removed with a mesh of 177 μm, and then fine particles were removed by passing through a mesh of 75 μm. Thus, cellulose particles A for formulations were obtained. Table 1 shows the particle size of the ground particles in the cellulose dispersion before drying and the physical properties of the cellulose particles A for formulation.

Example 2

Water was added to the ground cake-like product of Example 1, and the mixture was prepared into a cellulose dispersion having a solids content of 15% by weight using a homomixer. After adjusting the particle size, pH and IC, the dispersion was spray-dried under the same conditions as in Example 1. Coarse particles were removed with a mesh of 212 μm, and then fine particles were removed by passing through a mesh of 75 μm. Thus, cellulose particles B for formulations were obtained. Table 1 shows the particle diameters of the ground particles in the cellulose dispersion before drying and the physical properties of the cellulose particles B for pharmaceutical preparations.

Example 3

Water was added to the cake-like product having a solid content of 40% obtained in Example 1, and the mixture was prepared into a cellulose dispersion having a solid content of about 10% by weight using a homomixer. The dispersion was passed through a high-pressure crusher (MICROFLUIDIZERM-610 type, manufactured by Microfluidics Co.) three times under a pressure of 120 MPa, thereby completing the crushing treatment. After adjusting the particle size, pH, and IC, the dispersion was spray-dried under the same conditions as in Example 1, except that the air supply temperature was changed to 180°C. Coarse particles were removed with a mesh of 75 μm, and fine particles were removed with a mesh of 45 μm. Thus, cellulose particles C for formulations were obtained. Table 1 shows the particle diameters of the ground particles in the cellulose dispersion before drying and the physical properties of the cellulose particles C for pharmaceutical preparations.

Example 4

Water was added to the ground cake product obtained in Example 1, and the mixture was prepared into a cellulose dispersion having a solids content of about 18% by weight using a homomixer. After adjusting the particle size, pH and IC, the dispersion was spray-dried under the same conditions as in Example 1. Coarse particles were removed with a mesh of 212 μm, and fine particles were removed by passing through a mesh of 106 μm. Thus, cellulose particles D for formulations were obtained. Table 1 shows the particle diameters of the ground particles in the cellulose dispersion before drying and the physical properties of the cellulose particles D for pharmaceutical preparations.

Example 5

Commercially available dissolving pulp (abbreviated as DP hereinafter) was cut into chips, which were then hydrolyzed with 10% hydrochloric acid aqueous solution at 105° C. for 10 minutes. The resulting acid-insoluble residue was filtered and washed with water to obtain a cake-like product of microcrystalline cellulose having a solids concentration of about 40%. The cake-like product was ground with a universal mixer for 1 hour. Add water to it. A mixture of the ground cake product and water was prepared with a homomixer to give a cellulose dispersion having a solids content of 15% by weight. The dispersion was passed through a high-pressure crusher three times under a pressure of 120 MPa, thereby completing the crushing process. After adjusting the particle size, pH and IC, the dispersion was spray-dried under the same conditions as in Example 1, except that the rotation speed of the rotary disk was changed to 4000 rpm. Coarse particles were removed with a mesh of 300 μm, and fine particles were removed with a mesh of 177 μm. Thus, cellulose particles E for formulations were obtained. Table 1 shows the particle diameters of the ground particles in the cellulose dispersion before drying and the physical properties of the cellulose particles E for pharmaceutical preparations.

Example 6

Commercially available KP was cut into pieces, which were then hydrolyzed with 10% aqueous hydrochloric acid at 105°C for 60 minutes. The resulting acid-insoluble residue was filtered and washed with water to obtain a cake-like product of microcrystalline cellulose having a solids concentration of about 40%. The cake-like product was ground with a universal mixer for 1 hour. Add water to it. A mixture of the ground cake product and water was prepared with a homomixer to give a cellulose dispersion having a solids content of 13% by weight. The dispersion was passed through a high-pressure crusher three times under a pressure of 120 MPa, thereby completing the crushing process. After adjusting the particle size, pH and IC, the dispersion was spray-dried under the same conditions as in Example 1. Coarse particles were removed with a mesh of 150 μm, and then fine particles were removed by passing through a mesh of 63 μm. Thus, cellulose particles F for formulations were obtained. Table 1 shows the particle diameters of the ground particles in the cellulose dispersion before drying and the physical properties of the cellulose particles F for pharmaceutical preparations.

Example 7

Commercially available DP was cut into pieces and then hydrolyzed with 3% aqueous hydrochloric acid at 105 °C for 15 min. The resulting acid-insoluble residue was filtered and washed with water to obtain a cake-like product of microcrystalline cellulose having a solids concentration of about 40%. The cake-like product was ground with a universal mixer for 1 hour. Add water to it. A mixture of the ground cake product and water was prepared with a homomixer to give a cellulose dispersion having a solids content of 15% by weight. After adjusting the particle size, pH and IC, the dispersion was spray-dried under the same conditions as in Example 1. Coarse particles were removed with a mesh of 300 μm, and then fine particles were removed by passing through a mesh of 75 μm. Thus, cellulose particles G for formulations were obtained. Table 2 shows the particle size of the ground particles in the cellulose dispersion before drying and the physical properties of the cellulose particles G for formulation.

Example 8

The cake-like product obtained in Example 7 was ground for 30 minutes with a universal mixer. Add water to it. A mixture of the ground cake product and water was prepared with a homomixer to give a cellulose dispersion having a solids content of 20% by weight. After adjusting the particle size, pH and IC, the dispersion was spray-dried under the same conditions as in Example 1 except that the flow rate was changed to about 6.5 l/hour and the rotation speed of the rotary disk was changed to 2000 rpm. Coarse particles were removed with a mesh of 420 μm, and then fine particles were removed by passing through a mesh of 350 μm. Thus, cellulose particles H for pharmaceutical preparations were obtained. Table 2 shows the particle size of the ground particles in the cellulose dispersion before drying and the physical properties of the cellulose particles H for formulation.

Example 9

Water was added to the milled cake of Example 1, and the mixture was prepared into a cellulose dispersion having a solids content of 14% by weight using a homomixer. After adjusting the particle size, pH and IC, the dispersion was mixed with 12% by weight of lactose aqueous solution, the mixing ratio was 1000g dispersion to 500g lactose aqueous solution, and then the mixture was subjected to the same conditions as in Example 1. Spray dry. Coarse particles were removed with a mesh of 212 μm, and then fine particles were removed by passing through a mesh of 75 μm. Thus, the cellulose particles I for pharmaceutical preparations were obtained. Table 2 shows the particle diameters of the ground particles in the cellulose dispersion before adding the lactose aqueous solution and the physical properties of the cellulose particles I for pharmaceutical preparations.

Example 10

Water was added to the ground cake of Example 1, and the mixture was prepared into a cellulose dispersion having a solids content of 9% by weight using a homomixer. After adjusting the particle size, pH and IC, the dispersion was mixed with 9% by weight of lactose aqueous solution, the mixing ratio was 1000g dispersion to 1000g lactose aqueous solution, and then the mixture was subjected to the same conditions as in Example 1. Spray drying, just change the feed air temperature to about 180°C. Coarse particles were removed with a mesh of 150 μm, and then fine particles were removed by passing through a mesh of 63 μm. Thus, cellulose particles J for formulations were obtained. Table 2 shows the particle diameters of the ground particles in the cellulose dispersion before the addition of the lactose aqueous solution and the physical properties of the cellulose particles J for pharmaceutical preparations.

Example 11

Water was added to the ground cake of Example 1, and the mixture was prepared into a cellulose dispersion having a solids content of 8% by weight using a homomixer. After adjusting the particle diameter, pH and IC, the dispersion was mixed with a 17.1% by weight aqueous solution of lactose and a 3% by weight aqueous solution of hydroxypropylcellulose (L type, manufactured by Nippon Soda Co., Ltd.) , the mixing ratio was 500g dispersion liquid to 900g lactose solution to 200g hydroxypropyl cellulose solution, and then the mixture was spray-dried according to the same conditions as in Example 1, except that the air supply temperature was changed to about 180°C. Coarse particles were removed with a mesh of 150 μm, and then fine particles were removed by passing through a mesh of 75 μm. Thus, cellulose particles K for formulations were obtained. Table 2 shows the particle size of the ground particles in the cellulose dispersion before adding the lactose aqueous solution and the physical properties of the cellulose particles K for formulation.

Example 12

Water was added to the milled cake of Example 1, and the mixture was prepared into a cellulose dispersion having a solids content of 14.7% by weight using a homomixer. After adjusting the particle diameter, pH and IC, the dispersion was mixed with a 1.5% by weight aqueous solution of hydroxypropyl cellulose (L type, manufactured by Nippon Soda Co., Ltd.) in a mixing ratio of 1000 g of the dispersion Than 200g hydroxypropyl cellulose aqueous solution, then under the same conditions as in Example 1, the mixture was spray-dried. Coarse particles were removed with a mesh of 300 μm, and then fine particles were removed by passing through a mesh of 150 μm. Thus, cellulose particles L for formulations were obtained. Table 2 shows the particle diameters of the ground particles in the cellulose dispersion before adding the aqueous hydroxypropylcellulose solution and the physical properties of the cellulose particles L for formulation.

Example 13

The cake-like product with a solid content of about 40% obtained in Example 1 was ground with a universal mixer for 90 minutes. Water was added to the ground cake product, and the mixture was prepared into a cellulose dispersion having a solid content of 3% by weight using a homomixer. After adjusting the particle size, pH and IC, the dispersion was spray-dried using the same rotating disk as in Example 1. The drying operating conditions used were that the rotating speed of the rotating disk was about 25000 rpm, and the flow rate was about 3 l/hour. The air temperature is about 180°C and the exhaust temperature is about 85°C. Coarse particles were removed by a sieve with a mesh size of 38 μm to obtain cellulose particles M for pharmaceutical preparations. The cellulose particles M for formulation were found to have a tapped bulk density of 0.62 g/ml. Table 3 shows the particle size of the ground particles in the cellulose dispersion and the physical properties of the cellulose particles M for formulation.

Example 14

The cake-like product obtained in Example 6 was ground for 1 hour with a universal mixer. Water was added to the ground cake product, and the mixture was prepared into a cellulose dispersion having a solids content of 15% using a homomixer. The dispersion was passed through a high-pressure crusher three times under a pressure of 120 MPa, thereby completing the crushing process. After adjusting the particle size, pH and IC, the dispersion was spray-dried under the same conditions as in Example 1 except that the rotation speed of the rotary disk was changed to 4000 rpm. Coarse particles were removed with a mesh of 212 μm, and fine particles were removed with a mesh of 75 μm. Thus, cellulose particles N for formulations were obtained. The cellulose particles N for the formulation were found to have a tapped bulk density of 0.62 g/ml. Table 3 shows the particle diameters of the ground particles in the cellulose dispersion and the physical properties of the cellulose particles N for formulation.

Example 15

Water was added to the ground cake of Example 1, and the mixture was prepared into a cellulose dispersion having a solids content of 10.0% by weight using a homomixer. After adjusting the particle size, pH and IC, the dispersion was mixed with 10.0% by weight of lactose aqueous solution, 10.0% by weight of corn starch dispersion and 5.0% by weight of hydroxypropyl cellulose (L type, produced by NipponSoda Co. , Ltd.) to mix, the mixing ratio is 300g dispersion to 200g lactose solution, 480g cornstarch dispersion and 40g hydroxypropyl cellulose, then the mixture is spray-dried under the same conditions as in Example 1 , just change the air supply temperature to 180°C. Coarse particles were removed with a mesh of 150 μm, and then fine particles were removed by passing through a mesh of 75 μm. Thus, cellulose particles O for formulations were obtained. Table 3 shows the particle size of the ground particles in the cellulose dispersion before adding the lactose aqueous solution and the physical properties of the cellulose particles O for formulation.

Comparative example 1

Water was added to the cake-like product obtained in Example 1 having a solid content of about 40%, and the mixture was prepared into a cellulose dispersion having a solid content of 15% by weight using a homomixer. After adjusting the particle size, pH and IC, the dispersion was spray-dried under the same conditions as in Example 1. Coarse particles were removed with a mesh of 212 μm, and then fine particles were removed by passing through a mesh of 45 μm. Thus, cellulose particles P for formulations were obtained. Table 3 shows the particle diameters of the cellulose particles in the cellulose dispersion before drying and the physical properties of the particles P.

Comparative example 2

The commercially available DP was cut into pieces, and then hydrolyzed with 1% hydrochloric acid aqueous solution at 105°C for 10 minutes. The resulting acid-insoluble residue was filtered and washed with water to obtain a cake-like product of microcrystalline cellulose having a solids concentration of about 40%. The cake-like product was ground for 10 minutes with a universal mixer. Add water to it. The mixture of the ground cake product and water was formed into a cellulose dispersion having a solids content of 15% by weight with a homomixer. After adjusting the particle size, pH and IC, the dispersion was spray-dried under the same conditions as in Example 1. Coarse particles were removed by a sieve with a mesh of 300 μm, and then fine particles were removed by passing through a sieve with a mesh of 106 μm. Thus, cellulose particles Q for formulations were obtained. Table 3 shows the particle diameters of the ground particles in the cellulose dispersion before drying and the physical properties of the particles Q.

Comparative example 3

The cake-like product obtained in Comparative Example 2 was ground for 1 hour with a universal mixer. Add water to it. The mixture of the ground cake product and water was formed into a cellulose dispersion having a solids content of 10% by weight with a homomixer. The dispersion was passed through a high-pressure crusher three times under a pressure of 120 MPa, thereby completing the crushing process. After adjusting the particle size, pH, and IC, the dispersion was spray-dried under the same conditions as in Example 1, except that the supply air temperature was changed to 180°C. Coarse particles were removed with a mesh of 250 μm, and fine particles were removed by passing through a mesh of 75 μm. Thus, cellulose particles R for formulations were obtained. Table 3 shows the particle diameters of the ground particles in the cellulose dispersion before drying and the physical properties of the particles R.

Comparative example 4

According to the method disclosed in JP-A 7-173050, 1.5 kg of microcrystalline cellulose was put into a high-speed stirring granulator (FM-VG-10 type, manufactured by Powrex Co.), and 1.0 kg of of water, and knead the mixture for 5 minutes. 1 kg of the resulting wet pellets was transferred to a Malmerizer (Model Q-230, manufactured by Fuji Paudal Co., Ltd.), which was then rotated at a speed of 500 rpm for 10 minutes while spraying water at a speed of 10 g/min, thereby The particles were formed into spherical shapes. Thereafter, these spheres were dried at 40° C. for one day and one night in a hot air dryer (PV-211 type, manufactured by TabaiESPEC Co.). Coarse particles were removed with a mesh of 150 μm, and fine particles were removed with a mesh of 75 μm to obtain cellulose particles S for preparation. The physical properties of particles S are shown in Table 4.

Comparative Example 5

Particles were prepared in the same manner as in Comparative Example 4. Coarse particles were removed with a mesh of 212 μm, and fine particles were removed with a mesh of 106 μm to obtain cellulose particles T for preparation. The physical properties of particles T are shown in Table 4.

Comparative example 6

Preparation of particles was carried out in the same manner as in Comparative Example 4 except that the added water was increased to 1.2 kg. Coarse particles were removed with a mesh of 300 μm, and fine particles were removed with a mesh of 212 μm to obtain cellulose particles U for preparations. The physical properties of particles U are shown in Table 4.

Comparative Example 7

Particles V were obtained by passing commercially available crystalline cellulose (AVICEL (registered trademark) PH-200, manufactured by FMC Co.) through a sieve with an opening of 45 μm to remove fine particles. The physical properties of particle V are shown in Table 4.

Comparative Example 8

The waste rayon was chopped and then hydrolyzed with 10% aqueous hydrochloric acid at 100°C for 40 minutes. The resulting acid-insoluble residue was washed with hot water by decantation, and then it was prepared into a cellulose dispersion having a solid content of 10% by weight. After adjusting the particle size, pH, and IC, the dispersion was spray-dried under the same conditions as in Example 1, except that the supply air temperature was changed to 180°C. Coarse particles were removed with a mesh of 75 μm, and fine particles were removed with a mesh of 45 μm to obtain cellulose particles W for formulation. Table 4 shows the particle diameters of the ground particles and the physical properties of the particles W in the cellulose dispersion before drying.

Comparative Example 9

Commercially available sugar spherical core particles (NONPAREIL (registered trademark) NP101 "32-42" (refined sugar:corn starch=7:3), manufactured by Freund Industrial Co., Ltd.) were passed through a sieve with a mesh size of 420 μm Sieving was performed to remove coarse particles, whereby Particle X was obtained. The physical properties of particle X are shown in Table 4.

Example 16

1.0 kg of the cellulose particles for formulation obtained in Example 1 were prepared with a rotary fluidized bed type granulation coating machine ("MULTIPLEX" MP-01 type, manufactured by Powrex Co.) with a tangential bottom sprayer. A is fluidized for 20 minutes under the following conditions: rotation speed of the rotating disk: 450rpm, spray air pressure: 0.16MPa, spray air flow: 40l/min, protection air pressure: 0.20MPa, air supply temperature: room temperature (without heater) , Exhaust temperature: room temperature, air volume: 40m ³ /hour. Table 5 shows the results related to the fluidity, fragility, and adhesion of the particles to the bag filter.

Example 17

Particle B from Example 2 was fluidized under the same conditions as in Example 16 for 20 minutes. Table 5 shows the results related to the fluidity and friability of the particles and their attachment to the bag filter.

Comparative Example 10

The particles P obtained in Comparative Example 1 were fluidized under the same conditions as in Example 14 for 20 minutes. Table 5 shows the results related to the fluidity and friability of the particles and their attachment to the bag filter.

Comparative Example 11

Particles V obtained in Comparative Example 7 were fluidized under the same conditions as in Example 16 for 20 minutes. Table 5 shows the results related to the fluidity and friability of the particles and their attachment to the bag filter.

Example 18

Except that the air volume was changed to 50 m ³ /hour, under the same conditions as in Example 16, 1.0 kg of the cellulose particles H for preparation obtained in Example 8 were fluidized for 10 minutes, and the fluidity, brittleness and other characteristics of the particles were different. The results related to the attachment of the bag filter are shown in Table 6.

Comparative Example 12

Under the same conditions as those of Example 18, Particle X from Comparative Example 9 was fluidized for 10 minutes. The results related to the fluidity, friability of the particles and their attachment to the bag filter are shown in Table 6.

Example 19

With the MP-01 type that has improved Wuerster column, 1.0kg is obtained from the preparation cellulose particle C of embodiment 3 and fluidized 20 minutes under the following conditions: the air pressure of spraying: 0.16MPa, the air flow rate of spraying : 40l/min, side air pressure: 0.20MPa, side air discharge time: 0.2 seconds, side air stop time: 3.0 seconds, air supply temperature: room temperature (without heater), exhaust temperature: room temperature, air volume: ^30m3 /Hour. The results related to the fluidity, friability of the particles and their attachment to the bag filter are shown in Table 7.

Comparative Example 13

Under the same conditions as in Example 19, 1.0 kg of Particle K obtained in Comparative Example 8 was fluidized for 20 minutes. The results related to the fluidity, friability of the particles and their attachment to the bag filter are shown in Table 7.

Example 20

Under the same conditions as in Example 19, 1.0 kg of the cellulose particles M for formulation obtained in Example 13 were fluidized for 20 minutes. The results related to the fluidity, friability of the particles and their attachment to the bag filter are shown in Table 8.

Comparative Example 14

Under the same conditions as in Example 20, 1.0 kg of the particles P obtained in Comparative Example 1 were fluidized for 20 minutes, with a part of the particles being removed by passing through a sieve having a mesh size of 38 μm. The results related to the fluidity, friability of the particles and their attachment to the bag filter are shown in Table 8.

Example 21

The active ingredient comprising 3 parts of caffeine, 2 parts of hydroxypropyl cellulose (L type, manufactured by Nippon Soda Co., Ltd.) and 95 parts of water was dissolved in 5.5 g with a MP-01 type sprayer with a tangential bottom sprayer. Ratio per minute The preparation was sprayed to 0.5 kg of the cellulose particles A obtained from Example 1 for the preparation under the following conditions: rotating disk speed: 450 rpm, spray air pressure: 0.16 MPa, spray air flow: 40 l/min , Protection air pressure: 0.20MPa, air supply temperature: 75°C, exhaust temperature: 35°C, air volume: 30m ³ /hour, until the amount of caffeine layered on the cellulose particles for preparation reaches 2% by weight. The obtained granules were passed through a sieve with an opening of 177 μm, and the ratio of coarse particles to the granules was calculated. As shown in Table 9, it was demonstrated that layering of the active ingredient can be performed with little aggregation.

Comparative Example 15

Caffeine was layered on 0.5 kg of the particles S obtained in Comparative Example 4 under the same conditions as in Example 21. As shown in Table 9, it was found that aggregation occurred more easily than the cellulose particles A for formulation in Example 1.

Comparative Example 16

An active ingredient solution similar to that of Example 21 was injected into 0.5 kg of particles V from Comparative Example 7 (passed through a mesh of 177 μm) at a rate of 4.5 g/min with a MP-01 type tangential bottom sprayer. Coarse particles are removed by a sieve, and fine particles are removed by making it pass through a sieve with a mesh size of 75 μm) Spraying is carried out under the following conditions: rotating disk speed: 280rpm, spray air pressure: 0.13MPa, spray air Flow rate: 30 l/min, protective air pressure: 0.10 MPa, air supply temperature: 75°C, exhaust temperature: 36°C, air volume: 30m ³ /hr, until the amount of caffeine layered on the particles reaches 2% by weight. As shown in Table 9, it was found that aggregation occurred more easily than the cellulose particles A for formulation in Example 1.

Example 22

Under the same conditions as in Example 21, caffeine was layered on 0.5 kg of the cellulose particles B obtained in Example 2 until the amount of caffeine layered on the cellulose particles reached 2% by weight. The obtained particles were passed through a sieve with a mesh size of 212 μm, and the ratio of coarse particles to the particles was calculated. As shown in Table 10, it was demonstrated that layering of the active ingredient can be performed with little aggregation.

Comparative Example 17

Under the same conditions as in Example 22, caffeine was layered on 0.5 kg of the particles T obtained in Comparative Example 5 until the amount of caffeine layered on the particles reached 2% by weight. As shown in Table 10, it was found that aggregation occurred more easily than the cellulose particles B for formulation in Example 2.

Example 23

The active ingredient comprising 4 parts of caffeine, 5 parts of hydroxypropylcellulose (SL type, manufactured by Nippon Soda Co., Ltd.) and 91 parts of water was sprayed in 5.5 g with a MP-01 type with a tangential bottom sprayer. The ratio formulation per minute was used to spray 0.8 kg of the cellulose particles A obtained from Example 1 under the following conditions: rotating disk speed: 450 rpm, spray air pressure: 0.20 MPa, spray air flow: 40 l/min, Protective air pressure: 0.20 MPa, air supply temperature: 80°C, exhaust temperature: 37°C, air volume: 30m ³ /hour, until the amount of caffeine layered on the cellulose particles for preparation reaches 10% by weight. The obtained granules were passed through a sieve with a mesh size of 212 μm, and the ratio of coarse particles to the granules was calculated. As shown in Table 11, it was demonstrated that layering of the active ingredient can be performed with only little aggregation occurring.

Comparative Example 18

Under the same conditions as in Example 23, caffeine was layered on 0.8 kg of particles S from Comparative Example 4. As shown in Table 11, compared with the cellulose particle A for formulations of Example 1, aggregation was found to occur more easily.

Example 24

Under the same conditions as in Example 23, caffeine was layered on 0.8 kg of the cellulose particles B obtained in Example 2 until the amount of caffeine layered on the cellulose particles reached 10% by weight. The obtained granules were passed through a sieve with a mesh size of 250 μm, and the ratio of coarse particles to the granules was calculated. As shown in Table 12, it was demonstrated that layering of the active ingredient can be performed with little aggregation.

Comparative Example 19

Under the same conditions as in Example 23, caffeine was layered on 0.8 kg of the particles T obtained in Comparative Example 5 until the amount of caffeine layered on the particles reached 10% by weight. As shown in Table 12, it was found that aggregation occurred more easily than the cellulose particles B for formulation in Example 2.

Example 25

With MP-01 type with tangential bottom sprayer, the active ingredient comprising 4 parts of caffeine, 5 parts of hydroxypropyl cellulose (SL type, manufactured by Nippon Soda Co., Ltd.) and 91 parts of water was mixed at 9.0 The ratio of g/min is sprayed to 1.0kg from the particle G of Comparative Example 7 (a sieve with a mesh size of 212 μm has removed fine particles) under the following conditions: rotating disk speed: 450rpm, spray air pressure: 0.20MPa, Spray air flow rate: 40l/min, protective air pressure: 0.20MPa, air supply temperature: 80°C, exhaust temperature: 36°C, air volume: 40m ³ /hour, until the caffeine layered on the cellulose particles for the preparation up to 10% by weight. The obtained particles were passed through a sieve with a mesh size of 350 μm, and the ratio of coarse particles to the particles was calculated. As shown in Table 13, it was demonstrated that layering of the active ingredient can be performed with only little aggregation occurring.

Comparative Example 20

Caffeine was layered on 1.0 kg of particles U from Comparative Example 6 under the same conditions as in Example 25. As shown in Table 13, it was found that aggregation occurred more easily than the cellulose particles G for formulation in Example 7.

Example 26

Using an MP-01 type with a modified Wuster column, 10 parts of vitamin B ₂ , 2 parts of hydroxypropylcellulose (SL type, manufactured by Nippon Soda Co., Ltd.) and 88 parts of water were prepared. The dispersion of the active ingredient was sprayed at a rate of 5.0 g/min for the preparation of 0.8 kg of the cellulose particles M obtained from Example 13 under the following conditions: the air pressure of the spray: 0.20 MPa, the air flow rate of the spray: 40 l/ Minutes, side air pressure: 0.20MPa, side air discharge time: 0.2 seconds, side air stop time: 3.0 seconds, air supply temperature: 75°C, exhaust temperature: 37°C, air volume: 35m ³ /hour, until layered The amount of vitamin _B2 on the cellulose particles for the formulation was up to 2% by weight. The obtained particles were passed through a sieve with a mesh size of 38 μm, and the ratio of coarse particles to the particles was calculated. As shown in Table 14, it was confirmed that the layering of the active ingredient can be performed with only little aggregation occurring.

Comparative Example 21

With the MP-01 type with the improved Wuster column, except that the air pressure of the spray, the air flow rate of the spray and the air pressure of the side become 0.16MPa, 30l/min and 0.18Mpa respectively, in the same manner as in Example 21 Vitamin B ₂ was layered on 0.8 kg of the particles P obtained in Comparative Example 1 (part of the particles had been removed by sieving with a sieve having a mesh size of 38 μm) under the condition of . As shown in Table 14, it was found that aggregation occurred more easily than the cellulose particles M for formulations of Example 13.

Example 27

Layering of the active ingredient was performed twice under the same conditions as in Example 21, and the resulting granules were passed through a sieve with a mesh size of 177 μm to remove a part. Using the MP-01 type with tangential bottom sprayer, the coating liquid (solid content weight Ratio/ethyl cellulose aqueous dispersion: triacetin: D-mannitol=1.0: 0.25: 0.50) is sprayed on the granule prepared above 0.7kg under the following conditions: rotating disk speed: 450rpm, spray Air pressure: 0.18MPa, spray air flow rate: 40l/min, protective air pressure: 0.20MPa, air supply temperature: 70°C, exhaust temperature: 36°C, air volume: 40m ³ /hour, coating liquid feeding rate: 7g /min until the amount of solids coated on the granules reaches 25.0% by weight. The obtained coated granules were passed through a sieve with a mesh size of 212 μm, and the ratio of coarse particles to the coated granules was calculated. As shown in Table 15, it was demonstrated that coated particles could be obtained with only little aggregation occurring. The resulting pellets were heat-treated at 80° C. for 1 hour with a hot-air drier to complete film preparation, and thereafter were subjected to bitterness analysis by 10 panelists. As shown in Table 15, no bitterness was found even after 30 seconds, thus proving that it masks the bitterness.

Comparative Example 22

Layering of the active ingredient was performed twice under the same conditions as in Comparative Example 16. The resulting granules were passed through a sieve with a mesh size of 177 µm to remove a part of the particles, and then passed through a sieve with a mesh size of 75 µm to remove pulverized fine particles. With the MP-01 type that has tangential bottom sprayer, the coating solution identical with embodiment 18 is sprayed on the granule that prepares above 0.7kg under following conditions: rotating disk speed: 320rpm, the air pressure of spraying: 0.13 MPa, spray air flow rate: 30l/min, protective air pressure: 0.10MPa, air supply temperature: 70°C, exhaust temperature: 37°C, air volume: 40m ³ /hour, coating solution feeding speed: 6g/min, until The amount of solids coated on the granules was up to 25.0% by weight. The obtained coated granules were passed through a sieve with a mesh size of 212 µm, and then passed through a mesh with a mesh size of 75 µm to remove broken fine particles. Calculate the proportion of coarse particles to the coated granules. As shown in Table 15, it was found that aggregation occurred more easily than the particles obtained in Example 27. The resulting pellets were subjected to the same treatment as in Example 27 for thermal film formation. The resulting granules were subjected to the same bitterness analysis as in Example 27. As shown in Table 15, bitterness was found to develop after 30 seconds, proving that it could not mask the bitterness.

Example 28

50 parts of coated granules obtained in Example 27, 17 parts of D-mannitol, 30 parts of microcrystalline cellulose (Ceolus KG-802, manufactured by Asahi Chemical Industry Co., Ltd.), and 3 parts of cross-linked carboxyl Sodium methylcellulose was mixed in a plastic bag for 3 minutes, and then 0.5 g of the sample was put into the mortar of a compressor (TESTSTAND 1321DW-CREEP type, manufactured by AIKOHEngineering Co., Ltd.) with a bottom area of ¹ cm Compress with a flat pestle at a speed of 1 cm/min until the pressure reaches 10 MPa to obtain tablets containing granules. Bitterness analysis was performed by 10 panelists. Dissolution in the mouth was good, and bitterness was hardly detected even after 30 seconds. Therefore, it was confirmed that the bitterness was masked.

Comparative Example 23

Tablets containing granules were prepared in the same manner as in Example 28 except that 50 parts of the coated granules obtained in Comparative Example 22 were used. The resulting tablet was subjected to the same analysis as in Example 28. As a result, although the tablet dissolved well in the mouth, a bitter taste was found immediately after taking it, so it was proved that it could not mask the bitter taste.

Example 29

Using MP-01 type with tangential bottom sprayer, the active ingredient containing 10 parts of vitamin B ₂ , 2 parts of hydroxypropyl cellulose (SL type, manufactured by Nippon Soda Co., Ltd.) and 88 parts of water The dispersion was sprayed to 1.0 kg of the cellulose particles A obtained from Example 1 under the following conditions at 5.0 g/min: rotating disk speed: 450 rpm, spray air pressure: 0.16 MPa, spray air flow: 40 l/ Minutes, protective air pressure: 0.20MPa, air supply temperature: 75°C, exhaust temperature: 35°C, until the amount of vitamin _B2 layered on the cellulose particles for the preparation reaches 2% by weight. The obtained particles were passed through a sieve having an opening of 177 μm to remove a part of the particles. Subsequently, using the MP-01 type with a tangential bottom sprayer, the aqueous dispersion containing 38.1 parts of ethyl cellulose, 2.9 parts of triethyl citrate, 1.4 parts of hydroxypropyl methylcellulose (TC-5E, Coating liquid (manufactured by Shin-Etsu Chemical Co., Ltd.) and 59.6 parts of water (solid content weight ratio/ethylcellulose aqueous dispersion: triethyl citrate: TC-5E = 1.0: 0.25: 0.125 ) is sprayed onto 0.7kg of the particles prepared above under the following conditions: rotating disk speed: 450rpm, spray air pressure: 0.18MPa, spray air flow: 40l/min, protection air pressure: 0.20MPa, air supply temperature: 70 °C, exhaust temperature: 36 °C, air volume: 40m ³ /hour, feeding speed of coating liquid: 7g/min, until the amount of solids coated on the granules reaches 20.0% by weight. The obtained coated granules were passed through a sieve with an opening of 212 μm to remove coarse particles. The obtained particles were heat-treated with a hot air drier for 1 hour at 80° C. to complete the preparation of the film, and then according to the second dissolved substance test method in the 13th edition of the Japanese Pharmacopoeia (test solution: 900 ml of the 13th edition of the Japanese Pharmacopoeia General Test Method The first liquid in the disintegration test method, the rotation speed of the slurry: 100 rpm, was tested with an automatic dissolution tester DT-610 type, manufactured by JASCO Co.). When the dissolution rate of vitamin _B2 was measured by absorptiometry after 4 hours, the average value of 3 times was found to be 39%.

Comparative Example 24

With the MP-01 type that has tangential bottom sprayer, with embodiment 24 same layering active ingredient dispersion solution is obtained from the particle V of comparative example 7 under the following conditions to 1.0kg with the ratio of 5g/min Be that the sieve of 177 μm is removed coarse particle by mesh, and also be that the sieve of 75 μm removes fine particle) carry out spraying by mesh: rotating disk speed: 280rpm, the air pressure of spray: 0.13MPa, the air flow rate of spray: 30l/min, Protective air pressure: 0.10MPa, air supply temperature: 75°C, exhaust temperature: 36°C, air volume: 30m ³ /hour, until the amount of vitamin B ₂ coated on the cellulose particles for preparation reaches 2% by weight. The obtained coated granules were passed through a sieve with a mesh of 177 µm to remove a part of the particles, and then passed through a sieve with a mesh of 75 µm to remove pulverized fine particles. Subsequently, with the MP-01 type that has tangential bottom sprayer, the coating solution identical with embodiment 29 is sprayed on the granule prepared above 0.7kg under the following conditions: rotating disk speed: 320rpm, the air pressure of spraying : 0.13MPa, spray air flow rate: 30l/min, protective air pressure: 0.10MPa, air supply temperature: 70°C, exhaust temperature: 37°C, air volume: 40m ³ /hour, coating liquid feeding rate: 5.5g/ Minutes until the amount of solids coated on the granules reaches 20.0% by weight. The obtained coated granules were passed through a sieve with a mesh of 212 μm to remove coarse particles, and then passed through a sieve with a mesh of 75 μm to remove pulverized fine particles. After it was treated with the same heat treatment as in Example 24, a substance dissolution test was carried out. As a result, when the dissolution rate of vitamin _B2 after 4 hours was measured by absorptiometry, the average value of three times was found to be 82%. It was found that compared to the coated granules in Example 29, although the amount of coating was the same in each case, dissolution was not controlled in this case.

Table 1 Example 1A Example 2B Example 3C Example 4D Example 5E Example 6F Degree of polymerization of microcrystalline cellulose 153 153 153 153 245 135 Particle size of particles in cellulose dispersion [μm] 7 7 7 7 9 5 pH of the cellulose dispersion 7.0 7.1 6.9 7.2 6.8 7.3 IC of cellulose dispersion [μS/cm] 61 60 65 67 58 63 Loss on drying[%] 3.4 3.2 3.9 3.0 3.3 3.6 aspect ratio 0.85 0.85 0.87 0.81 0.78 0.89 Tapping bulk density [g/ml] 0.78 0.77 0.80 0.74 0.75 0.83 Angle of repose [°] 32 32 36 31 36 V30 shape factor 1.28 1.30 1.26 1.32 1.29 1.22 Average particle size [μm] 93 99 55 161 235 85 Load peak value [mN] 363 399 258 453 312 320 Specific surface area [m ² /g] 0.26 0.26 0.28 0.25 0.25 0.27 Water vapor adsorption[%] 2.54 2.53 2.73 2.45 2.39 2.67

Table 2 Example 7G Example 8H Example 9I Example 10J Example 11K Example 12L Degree of polymerization of microcrystalline cellulose 270 270 153 153 153 153 Particle size of particles in cellulose dispersion [μm] 12 14 7 7 7 7 pH of the cellulose dispersion 6.5 6.4 6.9 7.0 6.8 7.0 IC of cellulose dispersion [μS/cm] 55 57 66 64 60 68 Loss on drying[%] 3.5 3.4 3.8 3.8 3.5 2.9 aspect ratio 0.72 0.77 0.83 0.85 0.83 0.80 Tapping bulk density [g/ml] 0.68 0.64 0.79 0.80 0.77 0.73 Angle of repose [°] 38 37 31 33 34 31 shape factor 1.40 1.42 1.25 1.21 1.46 1.36 Average particle size [μm] 180 372 110 95 103 223 Load peak value [mN] 169 193 334 230 205 583 Specific surface area [m ² /g] 0.20 0.19 0.37 0.53 0.58 0.37 Water vapor adsorption[%] 1.95 1.72 2.50 2.50 2.42 2.39

table 3 Example 13M Example 14N Example 15O Comparative Example 1P Comparative Example 2Q Comparative example 3R Degree of polymerization of microcrystalline cellulose 153 135 153 153 400 400 Particle size of particles in cellulose dispersion [μm] 6 5 7 17 25 13 Ph of cellulose dispersion 7.3 7.1 7.1 7.1 7.5 7.4 IC of cellulose dispersion [μS/cm] 65 64 66 67 71 69 Loss on drying[%] 3.4 3.8 3.6 3.4 3.2 3.8 aspect ratio 0.78 0.84 0.82 0.83 0.65 0.71 Tapping bulk density [g/ml] 0.79 0.90 0.75 0.52 0.30 0.45 Angle of repose [°] 40 34 36 39 55 46 shape factor 1.11 1.28 1.36 1.46 1.59 1.55 Average particle size [μm] 25 123 107 128 222 165 Load peak value [mN] <50 465 172 111 95 125 Specific surface area [m ² /g] 0.30 0.28 0.49 0.69 0.75 0.62 Water vapor adsorption[%] 2.18 2.41 2.21 2.86 0.73 2.56

Table 4 Comparative Example 4S Comparative Example 5T Comparative Example 6U Comparative example 7V Comparative example 8W Comparative Example 9X Degree of polymerization of microcrystalline cellulose 240 240 240 242 55 - Particle size of particles in cellulose dispersion [μm] - - - - 3 - pH of the cellulose dispersion - - - - 7.5 - IC of cellulose dispersion [μS/cm] - - - - 74 - Loss on drying[%] 2.2 2.3 2.4 4.2 3.1 2.7 aspect ratio 0.90 0.90 0.91 0.75 0.86 0.91 Tapping bulk density [g/ml] 0.88 0.89 0.93 0.41 0.74 0.78 Angle of repose [°] 28 27 27 41 39 32 shape factor 1.07 1.07 1.08 1.53 1.35 1.51 Average particle size [μm] 136 165 245 153 59 378 Load peak value [mN] 667 724 1520 80 88 121 Specific surface area [m ² /g] 0.10 0.10 0.10 1.07 0.83 0.38 Water vapor adsorption[%] 0.87 1.84 0.60 2.76 1.89 1.31

table 5 Example 16 Example 17 Comparative Example 10 Comparative Example 11 nuclear particle A B P S fluidity good good good good particle brittleness Small Small big big Attachment to bag filter few few many many

Table 6 Example 18 Comparative Example 12 nuclear particle h x fluidity good good particle brittleness Small big Attachment to bag filter few many

Table 7 Example 19 Comparative Example 13 nuclear particle C W fluidity good good particle brittleness Small big Attachment to bag filter few many

Table 8 Example 20 Comparative Example 14 nuclear particle m P (through 38μm) fluidity good relatively good particle brittleness Small big Attachment to bag filter few many

Table 9 Example 21 Comparative Example 15 Comparative Example 16 nuclear particle A S V Definition of Coarse Particles Greater than 177μm Greater than 177μm Greater than 177μm Occurrence rate of coarse particles (%) 1.1 9.4 18.6

Table 10 Example 22 Comparative Example 17 nuclear particle B T Definition of Coarse Particles Greater than 212μm Greater than 212μm Occurrence rate of coarse particles (%) 1.0 7.8

Table 11 Example 23 Comparative Example 18 nuclear particle A S Definition of Coarse Particles Greater than 212μm Greater than 212μm Occurrence rate of coarse particles (%) 8.4 21.0

Table 12 Example 24 Comparative Example 19 nuclear particle B T Definition of Coarse Particles Greater than 250μm Greater than 250μm Occurrence rate of coarse particles (%) 5.3 16.3

Table 13 Example 25 Comparative Example 20 nuclear particle G (greater than 212μm) T Definition of Coarse Particles Greater than 350μm Greater than 350μm Occurrence rate of coarse particles (%) 3.0 10.3

Table 14 Example 26 Comparative Example 21 nuclear particle m P (through 38μm) Definition of Coarse Particles Greater than 38μm Greater than 38μm Occurrence rate of coarse particles (%) 13.0 32.2

Table 15 Example 27 Comparative Example 20 Granule preparation Example 21 Comparative Example 16 Definition of Coarse Particles Greater than 212μm Greater than 212μm Occurrence rate of coarse particles (%) 3.5 21.6 sensory analysis not bitter bitter

Industrial Applicability

The cellulose particles for preparations of the present invention have suitable tapping bulk density, suitable shape factor, high aspect ratio, suitable water vapor absorption and suitable particle strength, so they are very suitable for use as particles for preparations, especially suitable for active Core particles coated with ingredients.

Claims (11)

1. Cellulose particles for formulations comprising microcrystalline cellulose having an average degree of polymerization of 60 to 350 in an amount of not less than 10%, and which have a tapped bulk density of 0.60 to 0.95 g/ml, not less than 0.7 Aspect ratio, shape factor from 1.10 to 1.50, and average particle size from 10 to 400 μm. 2. The cellulose particle for formulation according to claim 1, wherein the particle has a specific surface area of 0.15 to 0.60 m ² /g. 3. The cellulose particles for formulations according to claim 1 or 2, wherein the particles have a moisture adsorption capacity of not less than 1.50%. 4. The cellulose particle for formulation according to any one of claims 1 to 2, wherein the particle has a peak load of 130 to 630 mN. 5. The cellulose particles for pharmaceutical preparations according to any one of claims 1 to 2, wherein the average particle diameter is 40 to 400 μm. 6. The cellulose particles for formulation according to any one of claims 1 to 2, wherein the shape factor is 1.15 to 1.50. 7. The cellulose particles for formulation according to any one of claims 1 to 2, wherein the tapped bulk density is 0.60 to 0.90 g/ml. 8. The cellulose particles for formulation according to any one of claims 1 to 2, wherein the tapped bulk density is 0.60 to 0.85 g/ml. 9. A method of preparing cellulose particles for formulation as claimed in any one of claims 1 to 8, the method comprising the steps of: hydrolyzing the cellulosic material to obtain a hydrolyzate having an average degree of polymerization of 60 to 350; subsequently grinding this hydrolyzate to obtain microcrystalline cellulose having an average particle diameter of not more than 15 μm; preparing a dispersion comprising the obtained microcrystalline cellulose; preparing said dispersion into droplets; and thereafter The droplets are dried. 10. The method as claimed in claim 9, wherein said dispersion comprising microcrystalline cellulose having a solid content of not less than 1% is prepared into droplets by using a rotating disk with a rotation speed of 500 to 30000 rpm, and then dried . 11. Spherical particles comprising the cellulose particles for formulation according to any one of claims 1 to 8, wherein an active ingredient is contained on the surface or inside of the spherical particles.